FOXO3a protects glioma cells against temozolomide-induced DNA double strand breaks via promotion of BNIP3-mediated mitophagy
| Autor: | Xuanzhong Wang, Meihua Piao, Zhen-chuan Wang, Tianfei Luo, Shi-peng Liang, Guangfan Chi, Shan Lu, Lei Wang, Chongcheng Wang, Pengfei Ge, Chuan He |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
BNIP3
mitochondrial superoxide Mice Nude Antineoplastic Agents temozolomide Mitochondrion medicine.disease_cause Article Mitochondrial Proteins DNA double strand break Downregulation and upregulation glioma Cell Line Tumor Proto-Oncogene Proteins Mitophagy medicine Autophagy oxidative stress Animals Humans Pharmacology (medical) DNA Breaks Double-Stranded FOXO3a Pharmacology Gene knockdown Mice Inbred BALB C Chemistry Forkhead Box Protein O3 Membrane Proteins General Medicine Cell biology Mitochondria Rats Up-Regulation bafilomycin A Cancer cell Apoptosis-inducing factor 3MA Oxidative stress |
| Zdroj: | Acta Pharmacologica Sinica |
| ISSN: | 1745-7254 1671-4083 |
| Popis: | FOXO3a (forkhead box transcription factor 3a) is involved in regulating multiple biological processes in cancer cells. BNIP3 (Bcl-2/adenovirus E1B 19-kDa-interacting protein 3) is a receptor accounting for priming damaged mitochondria for autophagic removal. In this study we investigated the role of FOXO3a in regulating the sensitivity of glioma cells to temozolomide (TMZ) and its relationship with BNIP3-mediated mitophagy. We showed that TMZ dosage-dependently inhibited the viability of human U87, U251, T98G, LN18 and rat C6 glioma cells with IC50 values of 135.75, 128.26, 142.65, 155.73 and 111.60 μM, respectively. In U87 and U251 cells, TMZ (200 μM) induced DNA double strand breaks (DSBs) and nuclear translocation of apoptosis inducing factor (AIF), which was accompanied by BNIP3-mediated mitophagy and FOXO3a accumulation in nucleus. TMZ treatment induced intracellular ROS accumulation in U87 and U251 cells via enhancing mitochondrial superoxide, which not only contributed to DNA DSBs and exacerbated mitochondrial dysfunction, but also upregulated FOXO3a expression. Knockdown of FOXO3a aggravated TMZ-induced DNA DSBs and mitochondrial damage, as well as glioma cell death. TMZ treatment not only upregulated BNIP3 and activated autophagy, but also triggered mitophagy by prompting BNIP3 translocation to mitochondria and reinforcing BNIP3 interaction with LC3BII. Inhibition of mitophagy by knocking down BNIP3 with SiRNA or blocking autophagy with 3MA or bafilomycin A1 exacerbated mitochondrial superoxide and intracellular ROS accumulation. Moreover, FOXO3a knockdown inhibited TMZ-induced BNIP3 upregulation and autophagy activation. In addition, we showed that treatment with TMZ (100 mg·kg−1·d−1, ip) for 12 days in C6 cell xenograft mice markedly inhibited tumor growth accompanied by inducing FOXO3a upregulation, oxidative stress and BNIP3-mediated mitophagy in tumor tissues. These results demonstrate that FOXO3a attenuates temozolomide-induced DNA double strand breaks in human glioma cells via promoting BNIP3-mediated mitophagy. |
| Databáze: | OpenAIRE |
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